Li Hong, Gu Zi-Kuan, Li Xiu-Sen, Hou Chun-Mei, Tang Pei-Hsien, Mao Ning
Department of Cell Biology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
Cell Transplant. 2007 Jan;16(1):85-95. doi: 10.3727/000000007783464470.
Previous data have demonstrated that mesenchymal stem cells (MSCs) can exert immunomodulatory activity in vitro, in which of the process nearly all kinds of immune cell subsets are involved. However, there is still a paucity of information about whether and why MSCs inhibit the ongoing immune responses in vivo. Working in a murine splenocyte transfusion model across the major histocompatibility barrier (C57BL/6 → BALB/c, H2b → H2d), we have found that MSC coinfusion prolongs the mean survival time (MST) of the recipient mice in a dose-dependent manner and reduces graft-versus-host-associated histopathology in comparison to the allosplenocyte transfusion controls. In vivo eGFP tracing with polymerase chain reaction analysis revealed that grafted MSCs could migrate and settle into the lungs, spleen, liver, intestine, and skin shortly after administration. Further investigations into the functional characteristics of intrasplenic lymphocytes showed that their proliferation and cytotoxic activity against P815 cells (H2d) were significantly restrained by MSC cotransfer. FACS analysis demonstrated that MSC infusion not only increased the proportion of CD4+ subset but also decreased that of CD8+ cells at the belated observation points, resulting in the increase of the ratio of CD4+/CD8+ cells. Also, in contrast to the slight increase of the proportion of CD4+CD25+ T regulatory cells (Tregs) in MSC cotransfer mice, the ratio of Tregs/CD8+ cells was dramatically elevated. Furthermore, RT-PCR analysis on the cytokine array of IL-2, IL-4, IL-12, TNF-α, and TGF-β in recipient splenocytes implied the Th1 to Th2 polarization. Therefore, it is deducible that alteration in the proportions of different T-lymphocyte subsets may be one of the main mechanisms by which grafted MSCs suppress the ongoing immune responses in vivo. The study here might provide some new clues for the design of therapeutic approaches for MSC transplantation.
先前的数据表明，间充质干细胞（MSCs）在体外可发挥免疫调节活性，该过程几乎涉及所有种类的免疫细胞亚群。然而，关于MSCs在体内是否以及为何抑制正在进行的免疫反应，仍然缺乏相关信息。在跨越主要组织相容性屏障（C57BL/6→BALB/c，H2b→H2d）的小鼠脾细胞输注模型中，我们发现与同种异体脾细胞输注对照组相比，共输注MSCs可剂量依赖性地延长受体小鼠的平均存活时间（MST），并减轻移植物抗宿主相关的组织病理学变化。通过聚合酶链反应分析进行的体内eGFP追踪显示，移植的MSCs在给药后不久即可迁移并定居于肺、脾、肝、肠和皮肤中。对脾内淋巴细胞功能特性的进一步研究表明，共转移MSCs可显著抑制其对P815细胞（H2d）的增殖和细胞毒性活性。流式细胞术分析表明，在较晚的观察点，输注MSCs不仅增加了CD4+亚群的比例，还降低了CD8+细胞的比例，导致CD4+/CD8+细胞比值升高。此外，与共转移MSCs小鼠中CD4+CD25+调节性T细胞（Tregs）比例略有增加相反，Tregs/CD8+细胞比值显著升高。此外，对受体脾细胞中IL-2、IL-4、IL-12、TNF-α和TGF-β细胞因子阵列的RT-PCR分析提示了Th1向Th2极化。因此，可以推断不同T淋巴细胞亚群比例的改变可能是移植的MSCs在体内抑制正在进行的免疫反应的主要机制之一。本研究可能为MSCs移植治疗方法的设计提供一些新线索。
